Fig. 4.

Schematic diagram of metabolic pathways and ¹³C labeling patterns related to reverse flux through pyruvate kinase in skeletal muscle after [U-¹³C₃]lactate administration. The direct conversion of [U-¹³C₃]lactate to [U-¹³C₃]pyruvate followed by reverse flux through pyruvate kinase results exclusively in [1,2,3-¹³C₃]- and [4,5,6-¹³C₃]glucose units in muscle glycogen without other labeling patterns. If phosphoenolpyruvate (PEP) formation from pyruvate occurs through a bypass (pyruvate → oxaloacetate → PEP) as seen in liver (Fig. 6, A and B), various glucose isotopomers including both [1,2,3-¹³C₃]- and [4,5,6-¹³C₃]glucose plus other distinctive labeling patterns such as [1,2-¹³C₂]glucose, etc. would be observed due to rearrangements of ¹³C in the TCA cycle and pyruvate cycling. The glutamate analysis of the tissue showed only [4,5-¹³C₂]-, [1,2-¹³C₂]-, and excess [3-¹³C₁]glutamate isotopomers. This informs that [U-¹³C₃]pyruvate incorporated into the TCA cycle only through pyruvate dehydrogenase but not through the pyruvate carboxylase pathway. PDH, pyruvate dehydrogenase; PK, pyruvate kinase; PC, pyruvate carboxylase; PEPCK, phosphoenolpyruvate carboxykinase; OAA, oxaloacetate; G3P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; a-kG, alpha-ketoglutarate. Open circle, ¹²C; filled circle, ¹³C.